Adverse Events in Patients Taking Cephalosporins Versus Placebo for Any Indication

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Adverse events in patients taking cephalosporins versus placebo for any indication

Mccullough, Amanda; Scott, Anna M.; Macindoe, Christopher; Clark, Justin; Hansen, Malene Plejdrup; Beller, Elaine M.; Aronson, Jeffrey K.; Del Mar, Chris B. Published in: Cochrane Database of Systematic Reviews

DOI: 10.1002/14651858.CD012435

Licence: Other

Link to output in Bond University research repository.

Recommended citation(APA): Mccullough, A., Scott, A. M., Macindoe, C., Clark, J., Hansen, M. P., Beller, E. M., Aronson, J. K., & Del Mar, C. B. (2016). Adverse events in patients taking cephalosporins versus placebo for any indication. Cochrane Database of Systematic Reviews, 2016(11), 1-10. [CD012435]. https://doi.org/10.1002/14651858.CD012435

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Download date: 27 Sep 2021 Cochrane Database of Systematic Reviews

Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol)

McCullough A, Scott AM, Macindoe C, Clark J, Hansen MP, Beller EM, Aronson JK, Del Mar CB

McCullough A, Scott AM, Macindoe C, Clark J, Hansen MP, Beller EM, Aronson JK, Del Mar CB. Adverse events in patients taking cephalosporins versus placebo for any indication. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD012435. DOI: 10.1002/14651858.CD012435. www.cochranelibrary.com

Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER...... 1 ABSTRACT ...... 1 BACKGROUND ...... 1 OBJECTIVES ...... 2 METHODS ...... 2 ACKNOWLEDGEMENTS ...... 5 REFERENCES ...... 5 APPENDICES ...... 6 CONTRIBUTIONSOFAUTHORS ...... 9 DECLARATIONSOFINTEREST ...... 9 SOURCESOFSUPPORT ...... 9

Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol) i Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Protocol] Adverse events in patients taking cephalosporins versus placebo for any indication

Amanda McCullough1, Anna M Scott1, Christopher Macindoe2, Justin Clark1, Malene Plejdrup Hansen3,4, Elaine M Beller1, Jeffrey K Aronson5, Chris B Del Mar1

1Centre for Research in Evidence-Based Practice (CREBP), Bond University, Gold Coast, Australia. 2Gold Coast University Hospital, Southport, Australia. 3Section of General Practice and Research Unit for General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 4Research Unit for General Practice in Aalborg and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark. 5Clinical Pharmacology, Oxford University, Oxford, UK

Contact address: Amanda McCullough, Centre for Research in Evidence-Based Practice (CREBP), Bond University, Gold Coast, Queensland, Australia. [email protected].

Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: New, published in Issue 11, 2016.

Citation: McCullough A, Scott AM, Macindoe C, Clark J, Hansen MP, Beller EM, Aronson JK, Del Mar CB. Adverse events in patients taking cephalosporins versus placebo for any indication. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD012435. DOI: 10.1002/14651858.CD012435.

ABSTRACT

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To quantify the incidence of any reported adverse event in patients taking cephalosporins compared with placebo for any indication.

Description of the intervention BACKGROUND Cephalosporins are a subclass of the β-lactams. The list of Inter- national Nonproprietary Names, compiled by the World Health Organization (WHO), contains 80 cephalosporins (WHO 2016), all of which share a common β-lactam ring and have medium to Description of the condition broad spectrum activity against both Gram-positive and Gram- negative bacterial species (Rang 2015), including Pseudomonas Use of cephalosporin antibiotics (known as cephalosporins) varies, aeruginosa (P aeruginosa), Streptococcus pneumoniae (S pneumo- with usage as low as 0.2% in Denmark and as high as 23.5% in niae), Staphylococcus aureus (S aureus), Haemophilus influenzae (H Malta (ECDC 2014). Variations in cephalosporin use may be due influenzae), Klebsiella pneumoniae (K pneumoniae), and Escherichia to concerns about the development of antibiotic resistance. Indica- coli (E coli)(Therapeutic Guidelines 2014). Cephalosporins are tions include: respiratory tract infections (acute otitis media, bac- often referred to as first, second, or third generation, based on the terial sinusitis, severe pneumonia), bacterial meningitis, urinary order in which they were developed. tract infections, septicaemia, surgical prophylaxis, skin and soft tis- An adverse event is an adverse outcome that occurs while a patient sue infections, and gonorrhoea (Australian Medicines Handbook is taking a drug, but the event is not (or not necessarily) attributable 2015).

Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol) 1 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. to the drug taken (Edwards 2000). Adverse events in those taking antibiotics are usually measured by It has been recommended that the recording of adverse events observational mechanisms: anecdotal reporting; voluntary organ- in clinical trials should distinguish suspected adverse effects from ised reporting; intensive event monitoring; and observational re- suspected adverse reactions (Aronson 2013), defined as follows. search studies (Edwards 2000). These approaches are susceptible 1. Adverse effects are unwanted outcomes of which the patient to reporting biases (Edwards 2000); and misclassification of the is not aware; they are usually detected by laboratory tests (e.g. cause of events which could be due to the antibiotic or the under- biochemical, haematological, immunological, radiological, lying disease for which it was prescribed. Randomised controlled pathological tests) or by clinical investigations (e.g. trials (RCTs) of antibiotics, the gold standard for determining ef- gastrointestinal endoscopy, cardiac catheterisation). ficacy of interventions, are often underpowered to detect differ- 2. Adverse reactions are unwanted outcomes that the patient ences in adverse events (Chen 2014). Several systematic reviews of experiences and are detected by their clinical manifestations RCTs in the Cochrane Library have reported on adverse events in (symptoms and/or signs). those taking cephalosporins (Kilburn 2010; Paul 2010), but noted 3. Serious adverse events are often reported separately. These that there were insufficient data on adverse events to make clear are adverse events that occur at any dose, and result in death or conclusions (Kilburn 2010). One way of overcoming this problem life-threatening events; requirement for hospitalisation or is to carry out a ‘multi-indication’ review i.e. a review of the effects prolongation of existing hospitalisation; persistent or significant of an intervention in all participants using the intervention for disability; or congenital anomalies; or are events that are any reason (indication). This type of review is particularly useful considered medically important (ICH 2003). for detecting rare events like adverse events, where the mechanism Recent guidance suggests that clinical trial authors should report of action is unrelated to the indication (Chen 2014). This review all adverse events that occur in more than 5% of any group (Zarin is the third in a series of multi-indication reviews investigating 2016). The events can be classified by the 27 System Organ Classes adverse events in those taking antibiotics (Gillies 2015; Plejdrup (e.g. blood and lymphatic system disorders) defined by the Medical Hansen 2015). Dictionary for Regulatory Activities (MedDRA) or the 335 High Level Group Terms of this classification (MedDRA 2016).

OBJECTIVES How the intervention might work Antibiotics can cause unwanted events in different ways. To quantify the incidence of any reported adverse event in patients 1. Hypersensitivity reactions, in which the host generates an taking cephalosporins compared with placebo for any indication. immune response to the drug, perhaps manifesting as a rash (Ibia 2000), and which can occur even at doses that are below the usual therapeutic range. METHODS 2. Adverse reactions that occur at doses in the usual therapeutic range (called collateral reactions). Some of these can occur through direct adverse effects (e.g. nausea and vomiting due to altered gastric emptying; Kuo 1998); and others through Criteria for considering studies for this review destruction of commensals (disturbing the equilibrium of the microbiome, which might cause diarrhoea from an overgrowth of Clostridium difﬁcile (C difﬁcile); or thrush from an Types of studies overgrowth of Candida). We will include randomised controlled trials (RCTs). We will ex- 3. Adverse reactions that occur at high doses (toxic reactions). clude pharmacodynamic studies of events that are not considered 4. Induction of antibiotic resistance in micro-organisms in the to be adverse events (e.g. studies that test gastrointestinal motil- microbiome, which may affect individuals in the general ity after ingestion of cephalosporins); pharmacokinetic studies of population. Since resistance can be transmitted between events that are not considered to be adverse events (e.g. testing organisms, the risk of harm from resistant micro-organisms interactions with other drugs); and studies with less than 20 par- extends beyond the individual. It is not possible to determine the ticipants randomised to each arm. extent of this harm from individually randomised trials, and this is therefore beyond the scope of the current review. Types of participants Why it is important to do this review We will include individuals of all ages taking cephalosporins for any indication.

Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol) 2 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Types of interventions the search strategy, we decided to supplement it with additional We will include trials comparing cephalosporins delivered by any terms. We did this using a four-step process. route (per oral, intravenous, intramuscular, or per rectal) with 1. We identified all cephalosporins listed in the Mesh database placebo. Use of concomitant medications is permitted. as well as any relevant entry terms from their MeSH entries and combined this list with the original list provided by the review author; this gave a list of 186 terms. Types of outcome measures 2. We removed trade names from the list; this left 127 terms. 3. Where a term contained an ’f’, for example, cefazolin, we added a new term using ’ph’ instead, for example, cephazolin. Primary outcomes This created a list of 206 terms. 4. One of the review authors (JA) undertook a final check of 1. A composite outcome of all adverse events of any kind (that the terms to remove any remaining trade names. This left 158 occur in 5% or more of any group; Zarin 2016). terms which were incorporated into the search strategy. 2. Serious adverse events. 3. Subsequent carriage of resistant bacteria (measured at any time point post-treatment). Searching other resources We will conduct a forward and backward citation analysis of all included studies to look for additional references. We will contact Secondary outcomes the authors of trials of cephalosporins versus placebo and ask for 1. Adverse events (that occur in 5% or more of any group; adverse events data if they are not published. Zarin 2016) organised by System Organ Classes listed in the MedDRA, and where there is enough information, High Level Terms of this classification (MedDRA 2016). Data collection and analysis Reporting one or more of the outcomes listed here in the trial is not an inclusion criterion for the review. Selection of studies Pairs of review authors (AMcC, AS, CM) will independently screen Search methods for identification of studies titles and abstracts resulting from the searches. We will retrieve all potentially eligible full-text articles for full-text screening. Pairs of review authors (AMcC, AS, CM) will independently screen the full-text and identify studies for inclusion, and identify and record Electronic searches reasons for exclusion of the ineligible studies. We will resolve any We will search the following databases from inception to present. disagreement through discussion or, if required, we will consult a 1. CENTRAL (Cochrane Central Register of Controlled third review author (CDM or EB). We will identify and exclude Trials). duplicates and collate multiple reports of the same study so that 2. PubMed (MEDLINE). each study rather than each report is the unit of interest in the 3. Embase. review. We will record the selection process in sufficient detail to We will use the search strategy described in Appendix 1 to complete a PRISMA flow diagram (Moher 2009), and ’Charac- search CENTRAL (Cochrane Central Register of Controlled Tri- teristics of excluded studies’ table. als), which contains the Cochrane Acute Respiratory Infections (ARIs) Group’s Specialised Register and PubMed (MEDLINE). We will use the Cochrane Highly Sensitive Search Strategy for Data extraction and management randomised trials: sensitivity and precision-maximising version Pairs of review authors (AMcC, AS, CM) will independently ex- (2008 revision) (Lefebvre 2011). We will adapt the search strat- tract the following data using a standardised data extraction form egy to search Embase. We will also conduct a search of the (piloted on at least one study in the review), which will include WHO International Clinical Trials Registry Platform (WHO the following information. ICTRP) (apps.who.int/trialsearch), which contains ClinicalTri- 1. Methods: study design, year of publication, clinical trial als.gov (www.ClinicalTrials.gov). We will not impose language, registration, study setting, study population, and information to publication date, or publication status restrictions. assess risk of bias (see below). To develop the search strategy, one of the review authors (JA) 2. Participants: N, mean age or age range, gender. provided a list of common cephalosporins from the WHO list of 3. Interventions: intervention (indication, route of International Nonproprietary Names (WHO 2016; see Appendix administration, dose, and duration), comparison, and 2). After an initial review of the search results using this list in concomitant medications.

Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol) 3 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4. Outcomes: any adverse events reported, times of Cochrane Handbook for Systematic Reviews of Interventions (Higgins measurements, and the methods used to elicit adverse events 2011): data. 1. when interventions effects are small; 5. Notes: funding for trial, and notable conflicts of interest of 2. when events are not particularly common; and trial authors. 3. the studies have similar numbers in the experimental and We will note in the ’Characteristics of included studies’ table if control group. outcome data are not reported in a usable way. We will resolve We will express ORs as absolute risk differences (RDs), based on disagreements by consensus or by involving a third review author assumed/average rates of adverse events in the control groups, and (CDM or EB). convert to the number needed to treat to harm (NNTH) to inter- pret the results from the meta-analysis. We will undertake meta- analyses only where this is meaningful, i.e. if the treatments, par- Assessment of risk of bias in included studies ticipants, and the underlying clinical question are similar enough Pairs of review authors (AMcC, AS, CM) will independently assess for pooling to make sense. risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving Unit of analysis issues another review author (CDM or EB). We will assess the risk of We will use the patient as the unit of analysis, where reported. If bias according to: antibiotic resistance is reported by proportion of isolated bacteria 1. random sequence generation; (rather than by patient), then we will use this as the unit of analysis. 2. allocation concealment; 3. blinding of participants and personnel; 4. blinding of outcome assessment; Dealing with missing data 5. incomplete outcome data; We will contact trial authors to obtain additional information 6. selective outcome reporting; and if reporting of data is incomplete or if the data are missing. If 7. other bias. no information about missing data is available, and the data are We will grade each potential source of bias as ’high’, ’low’ or ’un- thought to introduce bias, we will explore the impact of including clear’ and provide a quote from the study report together with a such studies in the overall results using a sensitivity analysis. justification for our judgement in the ’Risk of bias’ table. We will summarise the risk of bias judgements across different studies for each of the domains listed using a ’Risk of bias’ summary figure. Assessment of heterogeneity We will consider blinding separately for different key outcomes, We will use: (1) visual inspection of forest plots; (2) statistical test where necessary. Where information on risk of bias relates to un- of heterogeneity (Chi2 test); and, (3) measure of inconsistency (I² published data or correspondence with a trialist, we will note this statistic) to measure heterogeneity among the trials in each analysis. in the ’Risk of bias’ table. When considering treatment effects, we If we identify substantial heterogeneity (> 50%), we will report will take into account the risk of bias for the studies that contribute it and explore possible causes by prespecified subgroup analysis to that outcome. (Higgins 2011).

Assessment of bias in conducting the systematic Assessment of reporting biases review We will minimise reporting bias by conducting a comprehensive We will conduct the review according to this published protocol search for relevant study protocols and unpublished trials. Out- and report any deviations from it in the ’Differences between pro- come reporting bias may be particularly important for adverse tocol and review’ section of the systematic review. events, and we will clarify whether all outcomes listed in the study protocols are published and whether the outcomes were prede- ﬁned (Higgins 2011). If we are able to pool more than 10 trials, Measures of treatment effect we will create and examine a funnel plot to explore possible small Where possible, we will enter the outcome data for each study into study and publication biases. the data tables in Review Manager 5 to calculate the treatment effects (RevMan 2014). We plan to express all outcomes as Peto odds ratios (ORs), with accompanying 95% conﬁdence intervals Data synthesis (CIs), as we assume that the included trials will report few adverse We will pool data from studies we judge to be clinically homoge- events. However, we will only use this approach on condition of neous using Review Manager 5 software (RevMan 2014). If more meeting the relevant criteria for using Peto’s method as statedinthe than one study provides usable data in any single comparison, we

Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol) 4 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. will perform a meta-analysis. We will summarise every reported We plan to carry out the following subgroup analyses. adverse event with a meta-analysis of the OR using fixed-effects 1. Age groups (children or adults). models presented with 95% CIs. Where it is not possible to com- 2. First, second, or third generation of cephalosporin. bine data statistically, we will report outcomes narratively. 3. Route of administration (per oral, intravenous, intramuscular, per rectal). 4. Antibiotic dosage (dose and frequency of administration). GRADE and ’Summary of findings’ table 5. Duration of therapy. We will create a ’Summary of findings’ table which will include We will use the Chi² test to test for subgroup interactions in Review the following outcomes: a composite outcome of all adverse events Manager 5 (RevMan 2014). of any kind (that occur in 5% or more of any group; Zarin 2016); serious adverse events; subsequent carriage of resistant bacteria (measured at any time point post-treatment); and, adverse events Sensitivity analysis (that occur in 5% or more of any group; Zarin 2016) organised We will perform a sensitivity analysis by excluding those studies by System Organ Classes listed in the MedDRA, and where there found to have a high risk of bias. If a study has more than 20% of is enough information, High Level Terms of this classification randomised participants with missing data for the outcome (lost (MedDRA 2016). We will use the five GRADE considerations to follow-up/reporting of adverse events), we will exclude it from (study limitations, consistency of effect, imprecision, indirectness, the primary analysis, but include it in a sensitivity analysis. and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta-analyses for the prespecified outcomes (Atkins 2004). We will use methods and recommendations described in Section 8.5 and Chapter 12 ACKNOWLEDGEMENTS of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), using GRADEpro software (GRADEpro GDT We wish to thank the staff and editors of the Cochrane Acute Res- 2014). We will justify all decisions to down- or upgrade the quality piratory Infections (ARIs) Group and sincerely thank the follow- of studies using footnotes, and we will make comments to aid the ing people: Sheila Page, Nicholas Smith, David Andresen, Ravi reader’s understanding of the review where necessary. Shankar, and Paul Little for their feedback and suggested improve- ments to the protocol draft. The Methods section of this protocol is based on a standard template developed by the Cochrane Air- Subgroup analysis and investigation of heterogeneity ways Group and adapted by the Cochrane ARIs Group.

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Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol) 5 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Higgins 2011 meta-analyses: The PRISMA Statement. BMJ 2009;339: Higgins JP, Green S, editor(s). Cochrane Handbook 2535. for Systematic Reviews of Interventions Version 5.1.0 Paul 2010 (updated March 2011). The Cochrane Collaboration, Paul M, Yahav D, Bivas A, Fraser A, Leibovici L. Anti- 2011. Available from handbook.cochrane.org. pseudomonal beta-lactams for the initial, empirical, Ibia 2000 treatment of febrile neutropenia: comparison of beta- Ibia EO, Schwartz RH, Wiedermann BL. Antibiotic rashes lactams. Cochrane Database of Systematic Reviews 2010, in children: a survey in a private practice setting. Archives of Issue 11. [DOI: 10.1002/14651858.CD005197.pub3] Dermatology 2000;136(7):849–54. Plejdrup Hansen 2015 ICH 2003 Plejdrup Hansen MP, Thorning S, Aronson JK, Beller International Conference on Harmonisation. International EM, Glasziou P, Hoffmann TC, et al. Adverse events in conference on harmonisation of technical requirements patients taking macrolide antibiotics versus placebo for any for registration of pharmaceuticals for human use. Post- indication. Cochrane Database of Systematic Reviews 2015, approval safety data management: definitions and standards Issue 8. [DOI: 10.1002/14651858.CD011825] for expedited reporting. www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines/Efficacy/E2D/Step4/ Rang 2015 E2D_Guideline.pdf 2003 (accessed 09 November 2016). Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale’s Pharmacology. 8th Edition. London: Elsevier Kilburn 2010 Churchill Livingstone, 2015. Kilburn SA, Featherstone P, Higgins B, Brindle R. Interventions for cellulitis and erysipelas. Cochrane Database RevMan 2014 [Computer program] of Systematic Reviews 2010, Issue 6. [DOI: 10.1002/ Nordic Cochrane Centre, The Cochrane Collaboration. 14651858.CD004299.pub2] Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, Kuo 1998 2014. Kuo WH, Wadwa KS, Ferris CD. Cephalosporin antibiotics accelerate gastric emptying in mice. Digestive Diseases and Therapeutic Guidelines 2014 Sciences 1998;43(8):1690–4. Antibiotic Expert Groups. Antibiotic. Therapeutic Lefebvre 2011 Guidelines - Version 15. Melbourne: Therapeutic Guidelines Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching Limited, 2014. for studies. In: Higgins JP, Green S, editor(s). Cochrane WHO 2016 Handbook for Systematic Reviews of Interventions Version World Health Organization. International Nonproprietary 5.1.0 (updated March 2011). The Cochrane Collaboration, Names. www.who.int/medicines/services/inn/en/ (accessed 2011. Available from handbook.cochrane.org. 16 August 2016). MedDRA 2016 Zarin 2016 Medical Dictionary for Regulatory Activities. Zarin DA, Tse T, Williams RJ, Carr S. Trial reporting in www.meddra.org 2016 (accessed 09 November 2016). ClinicalTrials.gov - the final rule. New England Journal Moher 2009 of Medicine 2016 Sep 16 [Epub ahead of print]. [DOI: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA 10.1056/NEJMsr1611785] Group. Preferred reporting items for systematic reviews and ∗ Indicates the major publication for the study

Appendix 1. Pubmed (MEDLINE) search strategy (“Cephalosporins”[Mesh] OR Cephalosporins[tiab] OR Cephalosporin[tiab] OR Cephalosporanic[tiab] cefacetrile[tiab] OR cefadroxil[tiab] OR cefaclor[tiab] OR cefadroxil[tiab] OR cefalexin[tiab] OR cefaloglycin[tiab] OR cefalonium[tiab] OR cefaloram[tiab] OR cefaloridine[tiab] OR cefalotin[tiab] OR cefamandole[tiab] OR cefaparole[tiab] OR cefapirin[tiab] OR cefatriaxone[tiab] OR cefatrizine[tiab] OR cefazaflur[tiab] OR cefazedone[tiab] OR cefazolin[tiab] OR cefbuperazone[tiab] OR cefcanel[tiab] OR cefcapene[tiab] OR cefclidin[tiab] OR cefdaloxime[tiab] OR cefdinir[tiab] OR cefditoren[tiab] OR cefedrolor[tiab] OR cefempidone[tiab] OR cefepime[tiab] OR cefetamet[tiab] OR cefetecol[tiab] OR cefetrizole[tiab] OR cefiderocol[tiab] OR cefilavancin[tiab] OR cefivitril[tiab] OR cefixime[tiab] OR cefluprenam[tiab] OR cefmatilen[tiab] OR cefmenoxime[tiab] OR cefmepidium[tiab] OR cefmetazole[tiab] OR cefminox[tiab] OR cefodizime[tiab] OR cefonicid[tiab] OR cefoperazone[tiab] OR ceforanide[tiab] OR cefoselis[tiab] OR cefotaxime[tiab] OR cefotetan[tiab] OR cefotiam[tiab] OR cefovecin[tiab] OR cefoxazole[tiab] OR cefoxitin[tiab] OR cefozopran[tiab] OR cefpimizole[tiab] OR cefpiramide[tiab] OR cefpirome[tiab] OR cefpodoxime[tiab] OR cefprozil[tiab] OR cefquinome[tiab] OR cefradine[tiab] OR cefrotil[tiab] OR cefroxadine[tiab] OR cefsulodin[tiab] OR cefsumide[tiab] OR ceftaroline[tiab] OR ceftazidime[tiab] OR cefteram[tiab] OR ceftezole[tiab] OR ceftibuten[tiab] OR ceftiofur[tiab] OR ceftiolene[tiab] OR ceftioxide[tiab] OR ceftizoxime[tiab] OR ceftobiprole[tiab] OR ceftolozane[tiab] OR ceftriaxone[tiab] OR cefuracetime[tiab] OR cefuroxime[tiab] OR cefuzonam[tiab] OR cephacetrile[tiab] OR cephadroxil[tiab] OR cephaclor[tiab] OR cephadroxil[tiab] OR cephalexin[tiab] OR cephaloglycin[tiab] OR cephalonium[tiab] OR cephaloram[tiab] OR cephaloridine[tiab] OR cephalotin[tiab] OR cephamandole[tiab] OR cephaparole[tiab] OR cephapirin[tiab] OR cephatriaxone[tiab] OR cephatrizine[tiab] OR cephazaflur[tiab] OR cephazedone[tiab] OR cephazolin[tiab] OR cephbuperazone[tiab] OR cephcanel[tiab] OR cephcapene[tiab] OR cephclidin[tiab] OR cephdaloxime[tiab] OR cephdinir[tiab] OR cephditoren[tiab] OR cephedrolor[tiab] OR cephempidone[tiab] OR cephepime[tiab] OR cephetamet[tiab] OR cephetecol[tiab] OR cephetrizole[tiab] OR cephiderocol[tiab] OR cephilavancin[tiab] OR cephivitril[tiab] OR cephixime[tiab] OR cephluprenam[tiab] OR cephmatilen[tiab] OR cephmenoxime[tiab] OR cephmepidium[tiab] OR cephmetazole[tiab] OR ceph- minox[tiab] OR cephodizime[tiab] OR cephonicid[tiab] OR cephoperazone[tiab] OR cephoranide[tiab] OR cephoselis[tiab] OR cephotaxime[tiab] OR cephotetan[tiab] OR cephotiam[tiab] OR cephovecin[tiab] OR cephoxazole[tiab] OR cephoxitin[tiab] OR cephozopran[tiab] OR cephpimizole[tiab] OR cephpiramide[tiab] OR cephpirome[tiab] OR cephpodoxime[tiab] OR cephprozil[tiab] OR cephquinome[tiab] OR cephradine[tiab] OR cephrotil[tiab] OR cephroxadine[tiab] OR cephsulodin[tiab] OR cephsumide[tiab] OR cephtaroline[tiab] OR cephtazidime[tiab] OR cephteram[tiab] OR cephtezole[tiab] OR cephtibuten[tiab] OR cephtiofur[tiab] OR cephtiolene[tiab] OR cephtioxide[tiab] OR cephtizoxime[tiab] OR cephtobiprole[tiab] OR cephtolozane[tiab] OR cephtriaxone[tiab] OR cephuracetime[tiab] OR cephuroxime[tiab] OR cephuzonam[tiab]) AND (“Placebos”[Mesh] OR Placebos[tiab] OR Placebo[tiab] OR “Sham treatment”[tiab]) AND ((randomized controlled trial[Publication Type] OR controlled clinical trial[Publication Type] OR randomized[Title/Abstract] OR randomised[Title/Abstract] OR placebo[Title/Abstract] OR “drug therapy”[MeSH Terms] OR randomly[Title/Abstract] OR trial[Title/ Abstract] OR groups[Title/Abstract]) NOT (Animals[Mesh] not (Animals[Mesh] and Humans[Mesh]/)))

Appendix 2. List of all cephalosporin antibiotics (International Nonproprietary Names) cefacetrile cefaclor cefadroxil cefalexin cefaloglycin cefalonium cefaloram cefaloridine cefalotin cefamandole cefaparole cefapirin

Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol) 7 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. cefatrizine cefazaflur cefazedone cefazolin cefbuperazone cefcanel cefcanel daloxate cefcapene cefclidin cefdaloxime cefdinir cefditoren cefedrolor cefempidone cefepime cefetamet cefetecol cefetrizole cefiderocol cefilavancin cefivitril cefixime cefluprenam cefmatilen cefmenoxime cefmepidium chloride cefmetazole cefminox cefodizime cefonicid cefoperazone ceforanide cefoselis cefotaxime cefotetan cefotiam cefovecin cefoxazole cefoxitin cefozopran cefpimizole cefpiramide cefpirome cefpodoxime cefprozil cefquinome cefradine cefrotil cefroxadine cefsulodin cefsumide ceftaroline fosamil ceftazidime

Adverse events in patients taking cephalosporins versus placebo for any indication (Protocol) 8 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. cefteram ceftezole ceftibuten ceftiofur ceftiolene ceftioxide ceftizoxime ceftizoxime alapivoxil ceftobiprole ceftobiprole medocaril ceftolozane ceftriaxone cefuracetime cefuroxime cefuzonam

CONTRIBUTIONSOFAUTHORS

1. Chris Del Mar (CDM): conceived the original idea for this review. 2. Amanda McCullough (AMcC): was responsible for drafting the protocol. 3. All authors: contributed to the drafting of the protocol and agreed the ﬁnal version for publication.

DECLARATIONSOFINTEREST

1. Amanda McCullough: salary funded by the Centre for Research Excellence in Minimising Antibiotic Resistance from Acute Respiratory Infections (CREMARA) funded by the National Health and Medical Research Council (NHMRC), Australia. 2. Anna Scott: salary funded by the Centre for Research Excellence in Minimising Antibiotic Resistance from Acute Respiratory Infections (CREMARA) funded by the National Health and Medical Research Council (NHMRC), Australia. 3. Christopher Macindoe: none known. 4. Justin Clark: none known. 5. Malene Plejdrup Hansen: postdoc at Copenhagen Research Centre for Control of Antibiotic Resistance (UC-CARE), Denmark. 6. Elaine Beller: co-investigator on National Health and Medical Research Council (NHMRC) funded Centre for Research Excellence grant on antibiotic resistance. 7. Jeffrey K Aronson: JKA is a President Emeritus of the British Pharmacological Society, a Member of the Advisory Board of the British National Formulary, a Member of a Technology Appraisal Committee of the UK’s National Institute for Health and Care Excellence (NICE), Chair of the Expert Advisory Group on Nomenclature, British Pharmacopoeia Commission, and Editor of textbooks on adverse drug reactions, including ’Meyler’s Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions.’ He has published papers in peer-reviewed journals on different aspects of adverse drug reactions. 8. Chris Del Mar: Funding received from National Health and Medical Research Council (NHMRC) for the Cochrane Acute Respiratory Infections (ARIs) Group and for a Centre for Research Excellence in antibiotic resistance (which funded this review). Payment for board membership (ACP journal club). Consultancy fees for a small pharmaceutical company in Sydney, Australia for advice about registering a topical analgesic for otitis media, and BUPA for advisory work on shared decision-making. Royalties from books published by BMJ Books, Wiley-Blackwell. Travel expenses from Cochrane grants for going to Cochrane meeting, and from conference organisers to attend a conference as a presenter in Taiwan, 2010.

Internal sources • No sources of support supplied

External sources • National Health and Medical Research Council, Australia. Centre for Research Excellence in Minimising Antibiotic Resistance from Acute Respiratory Infections (CREMARA) (Grant 1044904)